Haoxuan Li, Yuhan Chen, Zhe Wang, Yankun Wang, Ran Bi, Jiayu Hou, Huan Chen, Zixuan Zhang, Zhenhao Guo, Zhuo Chen, Huixian Cui, Sha Li
INTRODUCTION: Hyperhomocysteinemia represents a modifiable risk factor for cognitive decline and dementia, yet the role of epigenetic aging mechanisms in mediating this association remain poorly characterized, limiting development of targeted interventions. METHODS: We analyzed 1343 National Health and Nutrition Examination Survey participants aged ≥ 60 years using weighted regression, cubic splines, and mediation analyses. An independent cohort of 2073 participants validated findings. RESULTS: Elevated homocysteine concentrations were significantly associated with reduced cognitive processing speed. GrimAge2 epigenetic age acceleration significantly mediated this association, accounting for 33.3% of the total effect. β2-microglobulin emerged as the strongest mediating component, explaining 38.8% of the homocysteine-cognition relationship. Folate demonstrated cognitive protection through homocysteine reduction (18.7% of total effect) without modulating downstream pathological cascades. CONCLUSION: Epigenetic aging-associated neuroinflammation serves as a key mechanistic link between hyperhomocysteinemia and cognitive decline. The neuroprotective effects of folate are mediated specifically through homocysteine reduction, providing novel mechanistic insights for precision prevention strategies in cognitive aging.